N-dealkylative SNAr reaction using aromatic halides: Synthesis of dihydrobenzoxazine and tetrahydrobenzoxazepine derivatives

Article abstract of DOI:10.1016/j.tet.2017.08.047

An efficient protocol for the synthesis of dihydrobenzoxazine and tetrahydrobenzoxazepine derivatives has been developed using haloarenes involving N-dealkylative S_NAr reaction. The method employs a wide variety of substrates and features the f

Full text of DOI:10.1016/j.tet.2017.08.047

Accepted Manuscript
N-dealkylative S Ar reaction using aromatic halides: Synthesis of
N
dihydrobenzoxazine and tetrahydrobenzoxazepine derivatives
Mosim Amin Pathan, Faiz Ahmed Khan
PII:
S0040-4020(17)30896-7
10.1016/j.tet.2017.08.047
TET 28941
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 26 April 2017
Revised Date: 23 August 2017
Accepted Date: 28 August 2017
Please cite this article as: Pathan MA, Khan FA, N-dealkylative S Ar reaction using aromatic halides:
N
Synthesis of dihydrobenzoxazine and tetrahydrobenzoxazepine derivatives, Tetrahedron (2017), doi:
10.1016/j.tet.2017.08.047.
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ACCEPTED MANUSCRIPT
Graphical Abstract
N-Dealkylative S Ar reaction using aromatic
Leave this area blank for abstract info.
N
halides: Synthesis of dihydrobenzoxazine
and tetrahydrobenzoxazepine derivatives
Mosim Amin Pathan and Faiz Ahmed Khan*
Department of Chemistry, Indian Institute of Technology Hyderabad, Kandi, Sangareddy, Telangana, 502 285,
India.

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
N-Dealkylative S Ar reaction using aromatic halides: Synthesis of
N
dihydrobenzoxazine and tetrahydrobenzoxazepine derivatives
Mosim Amin Pathan and Faiz Ahmed Khan ∗
Department of Chemistry, Indian Institute of Technology Hyderabad, Kandi, Sangareddy, Telangana, 502 285, India.
ARTICLE INFO
ABSTRACT
Article history:
Received
An efficient protocol for the synthesis of dihydrobenzoxazine and tetrahydrobenzoxazepine
derivatives has been developed using haloarenes involving N-dealkylative S Ar reaction. The
N
Received in revised form
Accepted
Available online
method employs a wide variety of substrates and features the formation of C-O and C−N bonds
in one-pot fashion. The products thus generated have been further transformed to m-terphenyls
by using Suzuki coupling reaction.
Keywords:
Dihydrobenzoxazine
Tetrahydrobenzoxazepine
Complementary pairing
Complementary ambiphile pairing
Cyclization
2009 Elsevier Ltd. All rights reserved.
—
——
∗
Corresponding author. Tel.: +91(40)23016084; e-mail: faiz@iith.ac.in

2
Tetrahedron
ACCEPTED MANUSCRIPT
a,b
1
. Introduction
Table 1. N-Dealkylative cyclization
Traditionally halogen atoms in organic molecules have served
as versatile functional groups to execute a number of synthetic
manoeuvres. The advent of transition metal catalyzed
transformations of organic halides in recent years, particularly for
creating C-C, C-heteroatom bonds, added a feather to this class,
1
making them highly sought after, inexpensive starting materials.
Moreover, a wide range of interesting biological profile exhibited
by naturally occurring organohalogens fascinated Chemists and
2
Biologists alike. Substantial number of newly reported marine
natural products are organobromine derivatives decorated in
3
numerous scaffolds.
Our group has actively taken up the task of synthesizing
4
brominated marine natural product and their analogs.
Dihydrobenzoxazine and tetrahydrobenzoxazepine core with six
and seven membered bicyclic ring having nitrogen, oxygen and
halogens are important constituents of pharmacophores and
5-7
biologically important molecules.
Owing to its biological
importance several synthetic protocols 8 of benzoxazine
preparation are known in the literature. However these
approaches demands harsh conditions, expensive catalyst and
lacks target specificity and generality.
9
Amphoteric molecules
with both electrophilic and
nucleophilic sites embedded into them have been utilized in
several domino reactions. Isocyanides are familiar example of
(1,1) class of amphoteric molecules and have been used in
several well-known transformations like Ugi and Passerini
10
reaction. Complementary ambiphile pairing (CAP) is a strategy
whereby two ambiphilic molecules having both electrophile and
nucleophile into them reacts with each other in a complementary
fashion (Figure 1). Hanson and co-workers have used this
interesting s1trategy for the synthesis of macrocyclic
1
heterocycles.
In continuation with our ongoing program of synthesizing
brominated marine natural product and their analogues we wish
to report a serendipitously observed strategy for synthesis of
functionalized benzoxazine employing complementary ambiphile
pairing (CAP) and complementary pairing (CP) methods (Figure
1
).
Figure 1. Graphical overview of our CAP and CP strategies.
a
Reaction conditions: Phenol 2a-2d (0.279 mmol), K CO
2
3
(
(
0.837 mmol), chlorodialkylamino hydrochloride 3a and 3b
0.390 mmol), 100-120 C, 4-36 h, 1 mL of DMF; Isolated
o
b
yields after column chromatography.
Figure 2. Examples of bioactive benzoxazine and organohalogens.
2
. Results and Discussion
For this purpose, tribromophenol 2a appeared to be a suitable
starting point. An etherification with 3-chloro-N,N-
Owing to biological importance of organohalogens and our
recent synthetic interest in brominated marine natural products
and their analogues, we became interested in (meta)isomeric
tribromo analogue of purpurealidin E (Figure 2).
dimethylpropan-1-amine hydrochloride 3a followed by a
4
sequence of Henry reaction, dehydration and reduction would
furnish the target molecule. In the reported synthesis of
purpurealidin E, the etherification was carried out on N-Boc-
12
protected 3,5-dibromo-4-hydroxyphenethylamine.
However,
.
when the above reaction was performed on 2a at room
temperature, no change (TLC monitoring) was observed but at

3
Cl
Me
HCl
Me
CN
elevated temperatures (Table 1) a new product
A
wa
C
s
C
de
E
tec
P
te
T
d.
E
T
D
he MANUSCRI
C
P
N
T
N
1
Br
Br
Br
Br
O
a
H
NMR spectrum of this chromatographically purified
Me
N
compound displayed some unusual spectral patterns which were
not supporting the formation of the expected etherified product
OH
Me
Br
Br
1
a. This eventually made us to use single-crystal X-ray data to
establish the structure as cyclized product 4a conclusively
Figure 3). It appears that etherified product 1a once formed is
b
2a
7
a
Ph
O
b
(
undergoing intramolecular N-dealkylative S Ar reaction to give
final cyclized product. In the same context 2-chloro-N,N-
dimethylethanamine hydrochloride 3b was treated with phenol
CNMe
N
CN
Me
Br
N
Br
Br
O
O
2
a under similar condition and we observed double fold increase
Me
Me
Br
N
in the yield of cyclized dihydrobenzoxazine derivative 4b along
with methylated by-product 5a in 21% yield (entry 2, Table 1).
The dihydrobenzoxazines are important motifs as exemplified by
a commercially available drug molecule levofloxacin having
antibiotic activity (Figure 2).
Ph
O
7a
7b
N-dealkylative
cyclization
PhOMe
CN
CN Me
N
Br
Br
Br
O
O
N
Br
Me
6a
4d
Scheme 1. Plausible reaction mechanism for the formation of
6
a and 4d.
As a logical step in the direction of improving the reaction
based on the above-mention observation was to devise a plan that
avoids the formation of by-product. At this stage we thought of
probing complementary pairing (CP) as an alternative general
strategy towards cyclized products. It was envisaged that attack
of a secondary amine on to the bis-electrophilic precursors 8a
would furnish the desired products via an intermediate similar to
1
3
Figure 3. Single crystal X-ray structure of compound 4a.
The by-product formed also gave us some insight into the
mechanism of the reaction. To test the feasibility of reaction,
,4,6-tribromo-3-hydroxybenzonitrile 2b when subjected to same
7
(Scheme 1). In addition to the ease of preparation of 8a and
2
avoidance of chloroamino-hydroclorides that have limited
commercial availability, absence a phenolic precursor that is
responsible for the by-product formation (Scheme 1) and hence
diminished yield, is the main advantages of this alternative
protocol. Accordingly, when phenol 2b was treated with 1,2-
dibromoethane under basic conditions, 8a was obtained in 92%
yield. Similarly, phenol 2b and 1,3-dibromopropane furnished 8b
in good yield and 2d gave 8c in 94% yield (Scheme 2). When
bis-electrophilic precursor 8a was subjected to dimethylamine at
ambient temperature, a formal (1+5) atom cyclized ortho and
para products 6a and 4d were obtained in good yield (Scheme 3).
On the other hand, reaction of 8a with diallylamine gave
selectively N-deallyllative para cyclized product 4g in 86%
yield. Similarly 8c gave 4f in 53% yield (Scheme 3).
condition gave seven membered cyclized product 4c in similar
yield (entry 3, Table 1). Interestingly, when phenol 2b was
treated with 3b, in addition to the usual cyclized product 4d, we
observed one more product with similar spectral pattern as 4d
except in aromatic region. Based on the spectral data, this was
assigned to be ortho cyclized product 6a (entry 4, Table 1).
Moreover, the reaction of dibromocynophenol 2c on treatment
with 3b gave expected cyclized product 4e along with methyl
protected phenol 5b (entry 5, Table 1). Similarly, phenol 2d
possessing a strong electron withdrawing nitro group gave
cyclized product 4f, though in 33% yield, but as a single
regioisomer (entry 6, Table 1). Based on the by-product obtained
5a, 6a and 5b) we proposed a plausible mechanism for product
formation (Scheme 1). The initially formed etherified compound
by nucleophilic halide displacement of 3a or 3b with phenol
a-2d has two possible modes of S Ar attack on benzene nucleus
ortho ‘a’ and para ‘b’) which will lead to two intermediates 7a
(
a,b
Scheme 2. Preparation of bis-electrophile
7
2
(
CN
CN
N
Br 5eq
Br
Br
Br
Br Br
Br
and 7b which on N-demethylation either by a bromide or
phenolate anion gives final products. The presence of electron
withdrawing group facilitates S Ar reaction at ortho- and para-
K
2
CO
3
, 3eq
O
OH
DMF
Br
Br
oC, 6h
60
2
a
8a, 92%
CN
N
14
positions.
CN
Br
Br
Br
5eq
Br
Br Br
K
Br
, 3eq
2
CO
3
O
Br
OH
DMF
60 C, 3h
Br
o
Br
8
NO
b, 71%
2
a
Br 5eq
2
NO
2
Br
Br
O
Br
Br
K
2
CO
3
, 3eq
Br
DMF
OH
o
6
0 C, 6h
Br
Br
8
c, 94%
2d
a
Reaction conditions: phenol (5.6 mmol), K CO 16.9 mmol,
2
3
o
b
dibromoalkane (28 mmol), 60 C, 3-5h, under N . Isolated yields
2
after column chromatography.

4
Tetrahedron
ACCEPTED MANUSCRIPT
After successfully demonstrating the advantage of CP method,
the next rational improvement was to avoid superfluous
dealkylative step by simply employing a primary instead of a
secondary amine. For this purpose, we planned to use primary
amines (Table 2). Accordingly, treatment of bis-electrophile 8a
with aqueous methylamine solution triggered the (1+5) atom
cyclization sequence, involving initial alkylation of methylamine
by primary alkyl bromide leading to a secondary amine followed
by intramolecular S Ar reaction, giving cyclized products 6a and
N
13
4
d (Table 2). The results with other primary amines are
Figure 4 Single crystal X-ray structure of compound 6h.
summarized in Table 2. The method tolerates various types of
functional groups like cyclopropyl 4m, 6h (Figure 4), CH O- 6i,
The ratio of ortho and para isomers varies depending on
amine used giving para cyclized benzoxazine as the major
product. To further investigate the scope of the cyclization
reaction and in order to diversify the strategy, we subjected bis-
electrophile 8b to similar conditions and we observed formal
(1+6) para cyclized product 4r, 4s and 4c in moderate yields
(Table 2).
3
4
n, -OH 6f, 4k, -NH 6g, 4i, allyl 6c, 4g with moderate to good
yield. Biologically important indole derivative tryptamine
worked smoothly and gave the products 6j and 4o in good yield.
Importantly in case of mono Boc-protected amine having primary
and secondary amine group into it, primary amine has selectively
reacted to yield products 6g, 4i in good yields. The method has
also been used to generate chiral cyclic product 4p, 4q by
employing chiral amines. Aryl amines failed to give the desired
products, which is perhaps due to the decreased nucleophilicity
of aryl amines.
Scheme 3. N-Dealkylative cyclization with secondary
a,b
amine.
CN Me
N
CN
CN
H
Br
Br
Br
O
N
Br
Br
O
Me
Me
Br
O
3h, rt
DMF
Br
N
Br
Me
8
a
H
N
6a, 30%
4d, 50%
CN
CN
Br
Br
O
Br
Br
O
Br
6 h, 85 o
DMF
3
C
Br
N
8
a
4g, 86%
NO
2
H
N
NO
2
Br
Br
O
Me
Me
Br
Br
O
Br
16h, 130 o
DMF
C
Br
N
8
c
Me
4f, 53%
a
Reaction conditions: 8a (0.108 mmol), diamine 10 equiv, rt-
o
b
8
5 C, 3-36h, 2mL of DMF, under air, Isolated yields after
column chromatography.
a,f,g
Table 2. Cyclization with primary amine

5
ACCEPTED MANUSCRIPT
a
b
c
d
e
Reaction conditions: 8a and 8b 0.216 mmol, 20 equiv of amine, 5 equiv of amine, 3 equiv of amine, 6 equiv of amine, 1mL of DMF, rt-110
o
f
g
C, 3-48 h, in case of 4p, 4q, 4r, 4s, 4c minor ortho isomer was not isolated; Isolated yields after column chromatography.

6
Tetrahedron
ACCEPTED MAdi
a,b
Table 3 Isolation of intermediate
N
hy
U
dro
S
b
C
en
R
zo
I
x
P
az
T
ine
and
tetrahydrobenzoxazepine.
The
method tolerates variety of functional groups. Notably, this work
represents, to the best of our knowledge, the first example of
intramolecular SNAr reaction for the synthesis of
dihydrobenzoxazine and tetrahydrobenzoxazepine derivatives in
an efficient manner featuring the formation of C-O and C-N
bonds in one-pot fashion.
4
. Experimental
4
.1. General information
In this section the preparations of all the compounds that have
been made in the course have been discussed. For the
experiments, all starting material and reagents are purchased
from standard commercial sources or were prepared in
laboratory. All the glassware were cleaned with soap water
followed by acetone and dried in hot air oven at 100 ˚C for 2h.
Solvents were distilled prior to use. IR spectra were recorded on
1
the Bruker Tensor 37 (FTIR) spectrophotometer. H NMR spectra
were recorded on Bruker Avance 400 (400 MHz) spectrometer at
2
95K in CDCl ; chemical shifts value (δ ppm) and coupling
3
a
constants (Hz) are reported in standard fashion with reference to
either tetramethylsilane (TMS) (δ-H = 0.00 ppm) or CHCl (δ-H
Reaction conditions: 8a (0.324mmol), amine (0.972), 2 mL DMF,
b
rt, under air, Isolated yields after column chromatography.
3
13
=
7.26 ppm). C NMR spectra were recorded on Bruker Avance
4
00 (100 MHz) spectrometer at 298K in CDCl ; chemical shifts
3
Most of the reactions proceeded at ambient temperature
however, the reaction with bulky amino groups required
elevated temperature. When compound 8a was treated with
bulky amines like diallyl, and chiral alpha methyl benzyl
amines at ambient temperature we were able to isolate
(
δ ppm) are reported relative to CHCl [(δ-C = 77.00 ppm)
3
13
central line of triplet]. In C NMR the nature of carbons (C, CH,
CH , and CH ) was determined by recording the DEPT- 135
2
3
1
spectra. In H NMR, the following abbreviations were used
throughout the experimental; s = singlet, d = doublet, t = triplet, q
=
The assignment of the signals was confirmed by H, C and
DEPT spectra. High resolution mass spectra (HRMS) were
recorded on Agilent 6538 UHD Q-TOF using multimode source
in +ESI method at the Department of Chemistry, Indian Institute
of Technology Hyderabad, India. Reactions were monitored by
TLC on silica gel (254 mesh) using a combination of hexane and
ethyl acetate as eluents.
intermediate 9a
reaction temperature resulted into completion of reaction to
give final cyclized product 4q 4p and 4g respectively.
, 9b and 9c (Table 3), which on raising the
quartet, qui = quintet, m = multiplet and br. s = broad singlet.
1 13
,
a,b
Table 4 Transformation of benzoxazines to m-terphenyls.
4
.2. Experimental procedures and spectral data for the
compounds 4a-4f:
4
.2.1. 7,9-dibromo-5-methyl-2,3,4,5-
tetrahydrobenzo[b][1,4]oxazepine-8-carbaldehyde
(
4a):
1
5
To a solution of 2,4,6-tribromo-3-hydroxybenzaldehyde 2a
(
100 mg, 0.279 mmol) in DMF (1 mL) was added K CO (115
2
3
mg, 0.837 mmol) and 2-Chloro-N,N-dimethylpropylamine
hydrochloride 3a (62 mg, 0.390 mmol) and the reaction mixture
o
was heated to 100 to 110 C for 24h. After completion of the
a
Reaction conditions: Pd(PPh ) (0.013mmol), PhB(OH)
0.13mmol), 2M K CO (aq) 0.2 mL, in 1 mL dioxane, under a N
2 3 2
b
3
4
2
reaction, water (3 mL) was added and the reaction mixture was
extracted with EtOAc (8x3 mL). Combined organic phases were
washed with water (2 mL), brine (2 mL), dried over sodium
sulfate, and concentrated in vacuo. The resulting crude was
purified over silica gel column chromatography with 15% EtOAc
in hexane, which afforded product as colourless solid (24 mg,
(
atmosphere, 80 °C, 10-12h, Isolated yields after column
chromatography.
Further, we aimed to synthesize m-terphenyls by the Suzuki
coupling reaction on few of the products thus generated via
CAP/CP cyclization strategy. The results are summarized in
Table 4.
o
1
25%); mp: 96-98 C; R = 0.5 (25% EtOAc in hexane); H NMR
f
(400 MHz, CDCl ) δ = 10.14 (s, 1H), 6.84 (s, 1H), 4.26 (t, J = 6.4
3
Hz, 2H), 3.57 (t, J=5.4Hz, 2H), 3.01 (s, 3H), 2.14 (quin, J=6.3
13
Hz, 2H); C NMR (100 MHz, CDCl ) δ = 190.4, 148.7, 144.5,
3
3
. Conclusions
1
2
21.6, 121.4, 121.3, 119.2, 69.8, 52.2, 41.2, 27.9; IR (neat) =
928, 2876, 1682, 1565, 1509, 1318, 1274, 1191, 1014, 909;
In conclusion, we have developed two methods for the
HRMS
(ESI+)
m/z
calculated
for
C H Br NO :
11 12 2 2
synthesis of dihydrobenzoxazine and tetrahydrobenzoxazepine in
moderate to good yield. We were successfully able to design CP
strategy which is superior to CAP strategy for synthesizing
+
3
47.9235[M+H] , found: 347.9224.
(4b and 5a):

7
To a solution of 2,4,6-tribromo-3-hydroxy
150 mg, 0.421 mmol) in DMF (1.5 mL) was added K CO (232
A
be
C
nz
C
al
E
de
P
hy
T
d
ED
e
2a MA
m
N
eth
U
yl
S
am
C
in
R
e
I
(
P
200mg, 2.5mmol) and the reaction mixture is
T
(
stirred for 4h at rt. To the reaction mixture then added water (4
mL) and extracted with EtOAc (8x3 mL)The combined organic
phases were washed with water (2 mL), brine (2 mL), dried over
sodium sulfate and concentrated in vacuo The resulting crude
was purified over silica gel column chromatography with 2%
EtOAc in hexane, which afforded product 4c (17 mg, 40%);
colourless solid; mp: 106-108 C; R = 0.2 (20% EtOAc in
hexane); H NMR (400 MHz, CDCl ) δ = 6.77 (s, 1H), 4.26 (t, J
= 6.3 Hz, 2H), 3.55 (t, J=5.4 Hz, 2H), 2.98 (s, 3H), 2.13 (quin, J
2
3
mg, 1.686 mmol) and 2-Chloro-N,N-dimethylethylamine
hydrochloride 3b (121 mg, 0.842 mmol) and the reaction mixture
o
is stirred at 100 C for 4h. After completion of reaction water (4
mL) was added into the reaction mixture and extracted with
EtOAc (8x3 mL), combined organic phases were washed with
water (2 mL), brine (2 mL), dried over sodium sulfate, and
concentrated in vacuo. The resulting crude was purified over
silica gel column chromatography with 20% EtOAc in hexane,
which afforded product 4b (60 mg, 56%) & 5a (19 mg, 21%).
o
f
1
3
13
= 6.3, 5.8 Hz, 2H); C NMR (100 MHz, CDCl ) δ = 148.7,
3
1
44.9, 120.8, 120.0, 117.8, 117.3, 106.6, 52.1, 41.2, 27.8; IR
4
.2.2. 6,8-dibromo-4-methyl-3,4-dihydro-2H-
(neat); 2960, 2216, 1573, 1501, 1337, 1279, 1189, 955, 727;
benzo[b][1,4]oxazine-7-carbaldehyde (4b):
+
HRMS calcd for C H Br N O: 344.9238, found [M+H]
o
11 11
2
2
Colourless solid; (60 mg, 56%); mp: 170-172 C; R = 0.5
f
:
344.923.
1
(20% EtOAc in hexane); H NMR (400 MHz, CDCl ) δ = 10.12
3
(s, 1H), 6.77 (s, 1H), 4.32 (t, J=4.4 Hz, 2H), 3.46 (t, J=4.4 Hz,
(4d and 6a):
13
To a solution of K CO (155 mg, 0.281 mmol) in DMF (2 mL)
2
1
2
9
H), 3.02 (s, 3H); C NMR (100 MHz, CDCl ) δ = 190.4, 140.9,
2
3
3
was added 2,4,6-tribromo-3-hydroxybenzonitrile 2b (81 mg,
.562 mmol) and 2-Chloro-N,N-dimethylethylamine
39.7, 119.9, 119.5, 114.6, 114.1, 64.3, 48.3, 38.3; IR (neat);
868, 2778, 1671, 1581, 1518, 1425, 1336, 1306, 1217, 1048,
26, 776; HRMS calcd for C H Br NO : 333.9078, found
0
hydrochloride 3b (155 mg, 1.124 mmol) and the reaction mixture
is heated to 100 C for 5h. After completion of reaction water (5
10
10
2
2
o
+
[
M+H] :333.9072.
mL) was added into the reaction mixture and extracted with
EtOAc (12x3 mL) combined organic phases were washed with
water (3 mL), brine (3 mL), dried over sodium sulfate, and
concentrated in vacuo. The resulting crude was purified over
silica gel column chromatography with 5-20% EtOAc in hexane,
4
.2.3. 2,4,6-tribromo-3-methoxybenzaldehyde (5a):
o
Colourless solid; (19 mg, 21%); mp: 98-100 C; R = 0.9 (20%
f
1
EtOAc in hexane); H NMR (400 MHz, CDCl ) δ = 10.15 (s,
3
13
1
1
3
1
H), 7.89 (s, 1H), 3.92 (s, 3H); C NMR (100 MHz, CDCl ) δ =
3
90.4, 154.7, 137.3, 133.5, 123.2, 118.8, 60.8; IR (neat);
066,2937, 2850, 1696, 1527, 1451, 1408, 1330, 1258, 1202,
which afforded product solid 4d (37 mg, 40%), Colourless solid;
o
mp: 178-180 C; R = 0.3 (10% EtOAc in hexane); as colourless
f
o
022, 1022, 920, 785, 747, 661, 633; HRMS calcd for
solid and 6a (9 mg, 10%), Colourless solid; mp: 156-158 C; R =
f
+
C H Br O : 370.7918, found [M+H] : 370.7909.
8
6
3
2
0.6 (10% EtOAc in hexane);
4
.2.4. 2,4,6-tribromo-3-hydroxybenzonitrile (2b):
Via dimethylamine addition
To a solution of Hydroxylamine hydrochloride (2.42 g, 34.85
mmol) in (45 mL) DMSO was added 2,4,6-tribromo-3-
The solution of 2,4,6-tribromo-3-(2-bromoethoxy)benzonitrile
8a (50 mg, 0.108 mmol) and 40% aq dimethyl amine (121 mg,
1.08 mmol) in DMF was stirred at rt for 3h. To the reaction
hydroxybenzaldehyde 2a (5 g, 13.94 mmol) and the reaction
o
mixture is heated to 100 C for 5h. The reaction mixture is then
mixture then added (4mL) H
EtOAc. The EtOAc layer is then washed with (3 mL) H
2
O and extracted with (8x3 mL)
O and (3
diluted with water (200 mL) and extracted with EtOAc (250x3
mL). The EtOAc layer is washed with water (60 mL) and brine
40 mL) solution, dried over sodium sulfate and concentrated on
2
mL) saturated brine solution after drying over sodium sulfate
reaction mixture is concentrated on rotavapour and purified on
(
rotavapour to give (4.89 g, 99%) 2,4,6-tribromo-3-
silica gel column using 20% EtOAc and hexane as eluent to give
o
hydroxybenzonitrile 2b which is usedo without further
4d (18 mg, 50%), Colourless solid; mp: 178-180 C; R
f
= 0.3 (10%
purification. Colourless solid; mp: 150-152 C; R = 0.2 (10%
EtOAc in hexane) and 6a (11 mg, 30%), Colourless solid; mp:
f
1
o
EtOAc in hexane); H NMR (400 MHz, MeOH-d ) δ =
.95(s,1H) ; C NMR (100 MHz, MeOH-d ) δ = 153.6, 137.0,
19.3, 118.7, 116.7, 116.3, 116.1; IR (neat); 3319, 2240, 1561,
524, 1436, 1378, 1285, 1175, 992, 868, 696; HRMS calcd for
156-158 C; R = 0.6 (10% EtOAc in hexane).
f
4
13
7
1
1
4
Via methylamine addition
To solution of 2,4,6-tribromo-3-(2-bromoethoxy)benzonitrile
8a (35 mg, 0.076 mmol) in DMF (0.5 mL) was added 40% aq
methylamine (120 mg, 1.52 mmol) and the reaction mixture is
stirred for 3h at rt. To the reaction mixture was then added water
(2 mL) and extracted with EtOAc (8x3 mL). The combined
organic phases were washed with water (2 mL), brine (2 mL),
dried over sodium sulfate and concentrated in vacuo. The
resulting crude was purified over silica gel column
+
C H Br N O: 370.8030, found [M+NH ] :370.8083.
7
6
3
2
4
4
.2.5. 7,9-dibromo-5-methyl-2,3,4,5-
tetrahydrobenzo[b][1,4]oxazepine-8-carbonitrile
4c):
To a solution of 2,4,6-tribromo-3-hydroxybenzonitrile 2b (100
mg, 0.281 mmol) in DMF (1.5 mL) was added K CO (155 mg,
(
2
3
1
.126
mmol)
and
2-Chloro-N,N-dimethylpropylamine
chromatography with 40% EtOAc in hexane, which afforded
o
hydrochloride 3a (89 mg, 0.562 mmol) and the reaction mixture
product 4d (11 mg, 44%), Colourless solid; mp: 178-180 C; R
f
=
o
is heated to 100 to 110 C for 36h. After completion of reaction
0.3 (10% EtOAc in hexane) and 6a (6 mg, 24%) Colourless solid;
o
water (6 mL) was added into the reaction mixture and extracted
with EtOAc (15x3 mL) combined organic phases was washed
with water (2 mL), brine (2 mL), dried over sodium sulfate, and
concentrated in vacuo. The resulting crude was purified over
silica gel column chromatography with 5% EtOAc in hexane,
mp: 156-158 C; R
= 0.6 (10% EtOAc in hexane).
f
4
.2.6. 6,8-dibromo-4-methyl-3,4-dihydro-2H-
benzo[b][1,4]oxazine-5-carbonitrile (6a):
o
Colourless solid; mp: 156-158 C; R = 0.6 (10% EtOAc in
f
1
hexane); H NMR (400 MHz, CDCl ) δ = 7.26 (s, 1H), 4.26 (t,
J=4.4 Hz, 2H), 3.35 (t, J=4.8 Hz, 2H), 3.26 (s, 3H); C NMR
3
which afforded product 4c (27 mg, 25%), colourless solid; mp:
13
o
1
06-108 C; R = 0.2 (20% EtOAc in hexane).
f
(
100 MHz, CDCl ) δ = 143.1, 142.6, 126.5, 117.4, 117.1, 116.0,
3
Via methyl amine addition
102.9, 63.0, 50.0, 43.7; IR (neat); 3096, 2941, 2211, 1575, 1502,
1425, 1367, 1307, 1226, 1056, 919, 817, 731; HRMS calcd for
To solution of 2,4,6-tribromo-3-(3-bromopropoxy)benzonitrile
+
8
b (60 mg, 0.125mmol) in DMF (2 mL) was added 40% aq
C H Br N O: 330.9082, found [M+H] :330.9083.
10
9
2
2

8
Tetrahedron
1
3
4
.2.7. 6,8-dibromo-4-methyl-3,4-dihydro-2H-
1H),7.29 (br.s, 1H); C NMR (100 MHz, CDCl ) δ = 150.3,
ACCEPTED MANUSCRIPT
3
benzo[b][1,4]oxazine-7-carbonitrile (4d):
135.2, 112.0, 103.7(2xC-Br), 102.5; (IR neat); 3470, 1610, 1542,
o
Colourless solid; mp: 178-180 C; R = 0.3 (10% EtOAc in hexane);
1444, 1356, 1302, 1198, 1160, 814, 673; HRMS calcd for
C H Br NNaO : 395.7483, found [M+Na]+ :395.7434.
f
1
H NMR (400 MHz, CDCl ) δ = 6.72 (s, 1 H), 4.33 (t, J = 4.4 Hz,
3
6
2
3
3
13
2
H), 3.47 (t, J = 4.8 Hz, 2H), 3.01 (s, 3 H); C NMR (100 MHz,
4
2
.2.12. 6,8-dibromo-4-methyl-7-nitro-3,4-dihydro-
H-benzo[b][1,4]oxazine (4f).
CDCl ) δ = 140.7, 139.9, 118.7, 117.5, 113.2, 113.0, 104.7, 64.4,
3
4
1
3
4
8.1, 38.3; IR (neat); 2921, 2857, 2215, 1589, 1520, 1428, 1346,
309, 1258, 1210, 1054, 927,809; HRMS calcd for C H Br N O:
30.9082, found [M+H] :330.9078.
.2.8. 2,4-dibromo-5-hydroxybenzonitrile (2c).
To a solution of 2,4,6-tribromo-3-nitrophenol 2d (65 mg,
10
9
2
2
+
0.171 mmol) in DMF (2 mL) was added K CO (94 mg, 0.684
mmol) and 2-Chloro-N,N-dimethylethylamine hydrochloride 3b
2 3
o
To solution of hydroxylamine hydrochloride (622 mg, 8.96 mmol) in
(49 mg, 0.342 mmol) and the reaction mixture is heated to 120 C
15
(3 mL) DMSO was added of 2,4-dibromo-5-hydroxybenzaldehyde
for 33h. After completion of reaction water (2 mL) was added
into the reaction mixture and extracted with EtOAc (12x3 mL)
combined organic phases were washed with water (3 mL), brine
(3 mL), dried over sodium sulfate, and concentrated in vacuo.
The resulting crude was purified over silica gel column
o
(1 g , 3.61 mmol) and the reaction mixture is heated to 100 C for 2h
.
The reaction mixture is then diluted with water (10 mL) and
extracted with EtOAc (25 x 3 mL). The EtOAc layer is washed with
water (6 mL) and brine (5 mL) solution dried over sodium sulfate
and concentrated on rotavapour to give 2c (940 mg , 95%) which is
used without further purification. Colourless solid (940 mg , 95%);
mp: 194-196 C; R = 0.3 (25% EtOAc in hexane); H NMR (400
MHz, MeOH-d ) δ = 7.87 (s, 1H), 7.18 (s, 1H); C NMR (100 MHz,
chromatography with 20% EtOAc in hexane, which afforded
product (4f) as yellow solid (30 mg, 32%); mp: 94-96 C; R =
o
f
o
1
1
f
0
6
.4 (25% EtOAc in hexane); H NMR (400 MHz, CDCl ) δ =
.72 (s, 1H), 4.38 (t, J=4.4Hz, 2H), 3.42 (t, J=4.4Hz, 2H), 2.98
13
3
4
MeOH-d ) δ = 155.8, 138.2, 121.4, 118.1, 117.6, 116.0, 114.4; IR
13
4
(s, 3H); C NMR (100 MHz, CDCl ) δ = 140.2, 138.6,
3
(neat); 3301,3082, 2238, 1575, 1477, 1389, 1252, 1206, 1062, 886,
+
113.0(2XCBr), 105.3, 102.7, 65.1, 48.0, 38.5; IR (neat);2920,
584, 1529, 1351, 1305, 1259, 1215, 1054, 923, 705; HRMS
8
2
(
62, 651; HRMS calcd for C H Br NO: 275.8660, found [M+H] :
7 4 2
1
75.8655.
4e) and (5b):
To a solution of 2,4-dibromo-5-hydroxybenzonitrile 2c (100
mg, 0.361 mmol) in DMF (1.5 mL) was added K CO (200 mg,
+
calcd for C H Br N O : 350.8980, found [M+H] :350.8973.
9
9
2
2
3
Via dimehylamine addition
2
3
The solution of 8c (900 mg, 1.91 mmol) and 40% aq dimethyl
amine (2.15 g, 19.1 mmol) in DMF (5mL) was stirred at 130 C
for 16h. To the reaction mixture then added (10mL) H O and
extracted with (25x3 mL) EtOAc. The EtOAc layer is then
1
3
1
.44 mmol) and 2-Chloro-N,N-dimethylethylamine hydrochloride
b (103 mg, 0.722 mmol) and the reaction mixture is heated to
00 to 120 C for 36h. After completion of reaction water (4 mL)
o
o
2
was added into the reaction mixture and extracted with EtOAc
12 x 3 mL) combined organic phases were washed with water (2
washed with (5 mL) H O and (5 mL) saturated brine solution
(
2
after drying over sodium sulfate reaction mixture is concentrated
on rotavapour and purified on silica gel column using 20%
EtOAc and hexane as eluent to give 4f (350 mg, 53%), as yellow
mL), brine (2 mL), dried over sodium sulfate, and concentrated in
vacuo. The resulting crude was purified over silica gel column
chromatography with 12% EtOAc in hexane, which afforded
product 4e (30 mg, 33%) and 5b (20 mg, 19%).
o
1
solid; mp: 94-96 C; R = 0.4 (25% EtOAc in hexane); H NMR
f
(
400 MHz, CDCl ) δ = 6.72 (s, 1H), 4.38 (t, J=4.4Hz, 2H), 3.42
3
13
4
.2.9. 6-bromo-4-methyl-3,4-dihydro-2H-
(t, J=4.4Hz, 2H), 2.98 (s, 3H); C NMR (100 MHz, CDCl ) δ =
3
benzo[b][1,4]oxazine-7-carbonitrile (4e):
1
40.2, 138.6, 113.0(2XCBr), 105.3, 102.7, 65.1, 48.0, 38.5; IR
o
Colourless solid (30 mg, 33%); mp: 138-140 C; R = 0.3
f
(neat);2920, 1584, 1529, 1351, 1305, 1259, 1215, 1054, 923,
1
+
(
25% EtOAc in hexane); H NMR (400 MHz, CDCl ) δ = 6.91
3
705; HRMS calcd for C H Br N O : 350.8980, found [M+H]
9
9
2
2
3
(
s, 1H), 6.72 (s, 1H), 4.23 (t, J=4.4 Hz, 2H), 3.41 (t, J=4.5 Hz,
:
350.8973.
13
2
1
2
1
2
H), 2.97 (s, 3H); C NMR (100 MHz, CDCl ) δ = 142.3, 141.0,
3
4
.3. Experimental procedures and spectral data for the
19.9, 118.6, 118.0, 114.3,101.2, 63.9, 48.2, 38.2; IR (neat);
945, 2897, 2217, 1604, 1524, 1347, 1314, 1263, 1220, 1164,
048, 917, 871, 669, 628; HRMS calcd for C H BrN O:
compounds 8a, 8b and 8c:
10
10
2
4
.3.1. 2,4,6-tribromo-3-(2-
+
52.9977, found [M+H] :252.9974.
bromoethoxy)benzonitrile (8a):
4
.2.10. 2,4-dibromo-5-methoxybenzonitrile (5b):
To stirred suspension of K CO (2.23 g, 16.9 mmol) in DMF
2
3
o
(
,
15 mL) was added 2,4,6-tribromo-3-hydroxybenzonitrile 2b (2 g
Colourless solid (20 mg, 19%); mp: 154-156 C; R = 0.8
f
o
1
5.6 mmol) and stirred at 0 C for 0.5 h. Then added 1,2-
(
25% EtOAc in hexane); H NMR (400 MHz, CDCl ) δ = 7.85
3
13
dibromoethane (5.32 g, 28 mmol) and after being stirred for 5 h
(s, 1 H), 7.10 (s, 1 H), 3.93 (s, 3 H); C NMR (100 MHz, CDCl3)
o
at 60 C to the reaction mix was added water (50 mL) and
δ = 155.8, 138.2, 121.4, 118.1, 117.6, 116.0, 114.4; IR (neat);
3
6
extracted with EtOAc (75x3 mL). The EtOAc layer is washed
with water (10 mL) and brine (10mL) solution dried over sodium
sulfate and evaporated under reduced pressure. The resulting
residue was purified over silica gel chromatography (10% EtOAc
084, 2979, 2229, 1577, 1467, 1356, 1253, 1164, 875, 852, 713+,
63; HRMS calcd for C H Br NO: 289.8816, found [M+H]
8
6
2
:
289.881.
4
.2.11. 2,4,6-tribromo-3-nitrophenol (2d):
in
hexane)
to
give
compound
2,4,6-tribromo-3-(2-
To a solution of m-nitrophenol (200 mg, 1.43 mmol) in water
2 mL) was added Bromine (0.3 mL, 5.75 mmol) and the reaction
bromoethoxy)benzonitrile 8a as colourless solid, (2.39 g, 92%);
o
1
(
mp: 95-97 C; R = 0.8 (10% EtOAc in hexane); H NMR (400
f
mixture is stirred at rt for 5h after completion of reaction (3 mL)
saturated sodium thiosulfate solution is added to quench
unreacted bromine and the reaction mix is extracted with EtOAc
MHz, CDCl ) δ = 7.89 (s, 1H), 4.35 (t, J=6.4 Hz, 2H), 3.72 (t,
3
13
J=6.4 Hz, 2H); C NMR (100 MHz, CDCl ) δ = 153.2, 136.4,
3
124.4, 123.1, 121.7, 119.4, 115.3, 72.7, 28.6; IR (neat); 3070,
2962, 2234, 1552, 1426, 1348, 1274, 1248, 1202, 1014, 1014,
947, 697, 603; HRMS calcd for C H Br N O: 476.7448, found
(18 mL) the EtOAc layer is washed with brine (3 mL) solution
dried over sodium sulfate and evaporated under reduced pressure
9
9
4
2
+
to give product 2d, Which is used without further purification.
[M+NH ] :476.7452.
4
o
Colourless solid (512 mg, 94%); mp: 150-152 C; R = 0.2 (20%
f
1
EtOAc in hexane); H NMR (400 MHz, CDCl ) δ = 7.80(s,
3

9
o
4
.3.2. 2,4,6-tribromo-3-(3-
Colourless solid (24 mg, 55%); mp: 166-168 C. R
EtOAc in hexane); H NMR (400 MHz, CDCl
f
= 0.2 (10%
) δ = 7.44 - 7.29 (m,
H), 7.24 - 7.15 (m, 2 H), 6.80 (s, 1H), 4.56 (s, 2H), 4.35 (t, J=4.4
ACCEPTED MANUSCRIPT
1
bromopropoxy)benzonitrile (8b):
3
3
To stirred suspension of K CO (3.5 g, 25.35 mmol) in DMF
2
3
13
Hz, 2H), 3.54 (t, J=4.4 Hz, 2H); C NMR (100 MHz, CDCl ) δ =
140.2, 139.8, 135.2, 129.2(2XCH), 128.0, 126.7(2XCH), 118.9,
17.4,113.8, 113.5, 105.0, 64.4, 54.3, 46.8; IR (neat); 3029, 2877,
3
(25 mL) was added 2,4,6-tribromo-3-hydroxybenzonitrile 2b (3 g
o
,
8.45 mmol) and stirred at 0 C for 0.5h. Then added 1,3-
1
dibromopropane (8.53 g, 42.25 mmol) and after being stirred for
3
extracted with EtOAc (100x3 mL). The EtOAc layer is washed
with water (10 mL) and brine (10 mL) solution dried over
sodium sulfate and evaporated under reduced pressure. The
resulting residue was purified over silica gel chromatography
o
2218, 1583, 1506, 1456, 1348, 1306, 1257, 1207, 1058, 923, 824,
h at 70 C to the reaction mix was added water (50 mL) and
+
7
29; HRMS calcd for C H Br N O: 406.9395, found [M+H]
16 13 2 2
:
406.9384.
(6c and 4g):
To solution of 2,4,6-tribromo-3-(2-bromoethoxy)benzonitrile
a (400 mg, 0.865 mmol) in DMF (2 mL) was added allyl amine
121 mg, 2.59 mmol) and the reaction mixture is stirred for 24h
at rt. To the reaction mixture was then added water (4 mL) and
extracted with EtOAc (8x3 mL). The combined organic phases
were washed with water (2 mL), brine (2 mL), dried over sodium
sulfate and concentrated in vacuo. The resulting crude was
purified over silica gel column chromatography with 40% EtOAc
8
(
(5% EtOAc in hexane) To give compound 2,4,6-tribromo-3-(3-
bromopropoxy)benzonitrile 8b as colourless solid (2.85 g, 71%);
mp: 98-100 C; R = 0.8 (10% EtOAc in hexane); H NMR (400
MHz, CDCl ) δ = 7.88 (s, 1H), 4.16 (t, J = 5.6 Hz, 2H), 3.71 (t, J
=
MHz, CDCl ) δ = 153.6, 136.4, 124.5, 123.2, 121.4, 119.3, 115.4,
7
1
o
1
f
3
13
6.6Hz, 2H), 2.42 (quin, J = 5.8, 6.4 Hz, 2H); C NMR (100
3
1.2, 33.1, 29.4; IR (neat); 3070,2950, 2886, 2235, 1552, 1525,
427, 1348, 1245, 1201, 1015, 878, 743, 696; HRMS calcd for
in hexane, which afforded product 6c (52 mg, 17%), Colourless
solid; mp: 84-86 C; R = 0.5 (10% EtOAc in hexane); & 4g (214
mg, 69%) Colourless solid (52 mg, 63%); mp: 124-126 C; R = 0.8
o
+
f
C H Br NO: 473.7339, found [M+H] : 475.7313.
o
10
8
4
f
(
15% EtOAc in hexane).
4
.3.3. 1,3,5-tribromo-2-(2-bromoethoxy)-4-
nitrobenzene 8c:
To stirred suspension of K CO (219 mg, 1.59 mmol) in DMF
Via diallylamine addition
2
3
The solution of 2,4,6-tribromo-3-(2-bromoethoxy)benzonitrile
a (50 mg, 0.108 mmol) and diallylamine (104 mg, 1.08 mmol)
(4 mL) was added 2,4,6-tribromo-3-nitrophenol 2d (200 mg,
8
o
o
0
.531 mmol) and stirred at 0 C for 0.5 h. Then added 1,2-
in DMF was heated with stirring at 85 C for 36 h. To the
reaction mixture then added (5 mL) H O and extracted with
(
dibromoethane (500 mg, 2.65 mmol) and after being stirred for
2
2
o
7 h at 80 C to the reaction mix was added water (8 mL) and
10x3 mL) EtOAc. The EtOAc layer is then washed with (3 mL)
extracted with EtOAc (75x3 mL). The EtOAc layer is washed
with water (3 mL) and brine (10 mL) solution dried over sodium
sulfate and evaporated under reduced pressure. The resulting
residue was purified over silica gel chromatography (10% EtOAc
in hexane) to give compound 1,3,5-tribromo-2-(2-bromoethoxy)-
H O and (3 mL) saturated brine solution after drying over sodium
sulfate reaction mixture is concentrated on rotavapour and
purified on silica gel column using 25% EtOAc in hexane as
2
eluent to give 4g (34 mg, 86%), Colourless solid (52 mg, 63%);
o
mp: 124-126 C; R = 0.8 (15% EtOAc in hexane).
f
4
-nitrobenzene 8c as colourless solid (242 mg, 94%); mp: 50-52
o
1
4.4.3. 4-allyl-6,8-dibromo-3,4-dihydro-2H-
C; R = 0.5 (10% EtOAc in hexane); H NMR (400MHz
f
benzo[b][1,4]oxazine-5-carbonitrile (6c):
,
3
CHLOROFORM-d) δ = 7.89 (s, 1H), 4.36 (t, J = 6.6 Hz, 2H),
.73 (t, J = 6.6 Hz, 2H); C NMR (101MHz ,CHLOROFORM-
o
13
Colourless solid; mp: 84-86 C; R = 0.5 (10% EtOAc in
f
1
hexane); H NMR (400 MHz, CDCl ) δ = 7.35 (s, 1H), 6.12 -
d) δ= 153.4, 136.4, 120.5, 111.2, 109.0, 72.9, 28.5; IR
neat);2962, 1542, 1355, 1247, 1001, 839, 704; HRMS (ESI+)
3
5
3
.98 (m, 1H), 5.40 - 5.26 (m, 2H), 4.24 (t, J=4.8 Hz, 2H), 3.98-
.96 (m, 2 H), 3.25 (t, J=4.4 Hz, 2H); C NMR (100 MHz,
(
13
+
m/z calculated for C H Br NNaO [M+H] : 505.6860; found:
8
5
4
3
CDCl ) δ = 143.5, 141.5, 133.5, 127.6, 119.2, 117.0, 116.5
5
05.6865.
3
1
1
8
16.4,105.3, 62.7, 59.3, 45.6; IR (neat); 3077,2980, 2881, 2221,
565, 1465, 1438, 1414, 1361, 1282, 1249, 1079, 1017, 928, 898,
22, 731; HRMS calcd for C H Br N O: 356.9238, found
4
.4. Experimental procedures and spectral data for the
compounds 6b, 4h, 6c, 4g, 6d, 4i, 6e, 4j, 6f, 4k, 6g, 4l, 6h, 4m, 6i,
m, 6j, 4o, 4p, 4q, 4r and 4s:
12
11
2
2
4
+
[
M+H] : 356.9228.
(
6b) and (4h): To
solution
of
2,4,6-tribromo-3-(2-
4
.4.4. 4-allyl-6,8-dibromo-3,4-dihydro-2H-
bromoethoxy)benzonitrile 8a (50 mg, 0.108 mmol) in DMF (1 mL)
was added benzyl amine (58 mg, 0.54 mmol) and the reaction
mixture is stirred for 8 h at 80 C. To the reaction mixture was then
added water (3 mL) and extracted with EtOAc (8x3 mL). The
combined organic phases were washed with water (2 mL), brine (2
mL), dried over sodium sulfate and concentrated in vacuo. The
resulting crude was purified over silica gel column chromatography
with 25% EtOAc in hexane, which afforded product 6b (7 mg, 16%);
benzo[b][1,4]oxazine-7-carbonitrile (4g):
o
o
Colourless solid; mp: 138-140 C. R
f
= 0.2 (10% EtOAc in
1
hexane); H NMR (400 MHz, CDCl ) δ = 6.72 (s, 1H), 5.79 (tdd,
J = 5.1, 10.3, 17.1 Hz, 1H), 5.23(dd, J=10.2, 17.6 Hz, 2H), 4.32
3
(
t, J=4.4 Hz, 2H), 3.95 (d, J=4.9 Hz, 2H), 3.49 (t, J=4.4 Hz, 2H);
1
3
C NMR (100 MHz, CDCl ) δ= 139.9, 139.8, 130.3, 118.8,
3
1
18.0, 117.5, 113.5, 113.5, 64.4, 53.1, 46.5; IR (neat); 3088,
&
4h (24 mg, 55%).
2879, 2216, 1583, 1511, 1458, 1349, 1308, 1260, 1208, 1063,
4
.4.1. 4-benzyl-6,8-dibromo-3,4-dihydro-2H-
926, 822; HRMS calcd for C12
[M+H] :356.9227.
H
11Br
2
N
2
O: 356.9238, found
+
benzo[b][1,4]oxazine-5-carbonitrile (6b):
Colourless solid (7 mg, 16%); mp: 98-100 C; R = 0.4 (10% EtOAc
in hexane); H NMR (400 MHz, CDCl ) δ = 7.61 - 7.10 (m, 6H),
o
f
(6d and 4i):
1
3
To solution of 2,4,6-tribromo-3-(2-bromoethoxy)benzonitrile
13
4
.56 (s, 2H), 4.19 (t, J=4.2 Hz, 2H), 3.12 (t, J=4.2 Hz, 2H);
C
8
a (60 mg, 0.129 mmol) in DMF (2 mL) was added
NMR (100 MHz, CDCl ) δ = 144.0, 141.2, 136.1, 128.8(2XCH),
3
cyclohexylamine (64 mg, 0.645 mmol) and the reaction mixture
1
4
7
28.6(2XCH), 128.4, 128.1, 117.0, 116.9, 116.2, 106.5, 62.2, 59.9,
5.1; IR (neat); 3064, 2940, 2224, 1563, 1438,1362, 1251, 1016,
33; HRMS calcd for C H Br N O: 406.9395, found [M+H]
o
is stirred for 6h at 60 C. To the reaction mixture then added
+
water (4 mL) and extracted with EtOAc (8x3 mL). The combined
organic phases were washed with water (2 mL), brine (2 mL),
dried over sodium sulfate and concentrated in vacuo. The
resulting crude was purified over silica gel column
16
13
2
2
:
406.939.
4
.4.2. 4-benzyl-6,8-dibromo-3,4-dihydro-2H-
benzo[b][1,4]oxazine-7-carbonitrile (4h):

1
0
Tetrahedron
chromatography with 40% EtOAc in hexan
product 6d (8 mg, 15%) & 4i (25 mg, 53%).
A
e,
C
w
C
hic
E
h
P
af
T
fo
E
rd
D
ed MAco
N
nc
U
ent
S
ra
C
ted
R
i
I
n vacuo. The resulting crude was purified over silica
PT
gel column chromatography with 15% EtOAc in hexane, which
afforded product 6f (23 mg, 20%) & 4k (90 mg, 77%).
4
.4.5. 6,8-dibromo-4-cyclohexyl-3,4-dihydro-2H-
4
2
.4.9. 6,8-dibromo-4-(2-hydroxyethyl)-3,4-dihydro-
H-benzo[b][1,4]oxazine-5-carbonitrile (6f):
benzo[b][1,4]oxazine-5-carbonitrile (6d):
o
o
Colourless solid (8 mg, 15%); mp: 134-136 C; R = 0.4(10%
f
Colourless solid (23 mg, 20%); mp: 98-100 C. R = 0.3 (10% EtOAc
in hexane); H NMR (400 MHz, CDCl ) δ = 7.32 (s, 1H), 4.27 (t,
J=4.4 Hz, 2H), 4.04 (t, J=5.8 Hz, 2H), 3.59 (t, J=5.8 Hz, 2H), 3.44 (t,
J=4.8 Hz, 2H), 2.44(s, 1H); C NMR (100 MHz, CDCl ) δ = 143.3,
141.7, 127.3, 117.2, 117.1, 116.7, 104.0, 62.8, 61.6, 57.8, 47.8; IR
(neat); 3429, 2929, 2880, 2218, 1566, 1466, 1438, 1361, 1290, 1233,
1029, 916, 830, 784, 732, 615; HRMS calcd for C11H11Br N O :
f
1
1
EtOAc in hexane); H NMR (400 MHz, CDCl ) δ = 7.26(s, 1H),
3
3
4
2
=
.21(t, J = 4.4 Hz, 2H), 4.07 - 3.88 (m, 1H), 3.3(t, J = 4.8 Hz,
H), 1.95(d, J = 10.2Hz, 2H), 1.85(d, J = 11.7 Hz, 2H), 1.69(d, J
13
3
1
3
11.2Hz, 1H), 1.52-1.35(m, 4H), 1.14-1.04 (m,1H); C NMR
(100 MHz, CDCl )δ = 142.7, 141.5, 126.0, 117.1, 116.9,
3
1
16.0,103.4, 65.4, 63.2, 40.5, 31.1(2xCH ), 25.7(2xCH ), 25.4;
2 2 2
2
2
+
3
4
60.9187, found [M+H] :360.9174.
.4.10. 6,8-dibromo-4-(2-hydroxyethyl)-3,4-
IR (neat); 2929, 1564, 1441, 1348, 1248, 1037; HRMS calcd for
C H Br N O: 398.9708, found [M+H] :398.9697.
+
15
17
2
2
dihydro-2H-benzo[b][1,4]oxazine-7-carbonitrile
4k):
4
.4.6. 6,8-dibromo-4-cyclohexyl-3,4-dihydro-2H-
(
benzo[b][1,4]oxazine-7-carbonitrile (4i):
o
Colourless solid (90 mg, 77%); mp: 154-156 C; R = 0.2 (25%
EtOAc in hexane); H NMR (400MHz ,DMSO-d ) δ = 7.09 (s, 1H),
4.84 (t, J = 4.9 Hz, 1H), 4.32 - 4.16 (m, 2H), 3.57 (dd, J = 4.6, 13.0
Hz, 4H), 3.49 (d, J = 4.9 Hz, 2H); C NMR (100 MHz, DMSO-d ) δ
f
o
1
Colourless solid (25 mg, 53%); mp: 192-194 C; R = 0.2
f
6
1
(10% EtOAc in hexane); H NMR (400 MHz, CDCl ) δ =
3
13
6
.75(s,1H), 4.24 (t, J = 4.4 Hz, 2H), 3.55 (m, 1H), 3.41(t, J = 4.4
6
Hz, 2H), 1.92-1.89 (m, 2H), 1.81-1.73 (m, 3H), 1.47-1.39 (m,
= 140.9, 139.3, 118.2, 117.8, 113.1, 112.2, 100.9, 63.9, 57.7, 52.4,
46.9; IR (neat); 3395, 2216, 1654, 1583, 1513, 1419, 1349, 1263,
13
4
1
2
1
H), 1.18-1.14(m, 1H); C NMR (100 MHz, CDCl ) δ =140.1,
39.9, 118.9, 117.6, 113.6, 113.1, 103.8, 64.6, 56.6, 39.9,
9.3(2xCH2), 25.7(2xCH2), 25.5; IR (neat); 2931, 2857, 2218,
3
1
022, 998, 731; HRMS calcd for C H Br N O : 360.9187, found
11 11 2 2 2
+
[
M+H] :360.9182.
6
g and 4l:
580, 1499, 1310, 1255, 1205, 1062, 940, 732; HRMS calcd for
+
To solution of 2,4,6-tribromo-3-(2-bromoethoxy)benzonitrile
C H Br N O: 398.9708, found [M+H] :398.9675.
15
17
2
2
8
a (300 mg, 0.65 mmol) in DMF (2 mL) was added tert-butyl 3-
(6e and 4j):
aminopropylcarbamate (331 mg, 1.95 mmol) and the reaction
mixture is stirred for 48h at rt. To the reaction mixture then
added water (8 mL) and extracted with EtOAc (15x3 mL). The
combined organic phases were washed with water (5 mL), brine
To solution of 2,4,6-tribromo-3-(2-bromoethoxy)benzonitrile
8
a (100 mg, 0.216 mmol) in DMF (1 mL) was added butylamine
(79 mg, 1.082 mmol) and the reaction mixture is stirred for 20h
at rt. To the reaction mixture then added water (3 mL) and
extracted with EtOAc (8x3 mL). The combined organic phases
were washed with water (2 mL), brine (2 mL), dried over sodium
sulfate and concentrated in vacuo. The resulting crude was
purified over silica gel column chromatography with 15% EtOAc
in hexane, which afforded product 6e (15 mg, 19%); & 4j (52
mg, 63%).
(
5 mL), dried over sodium sulfate and concentrated in vacuo. The
resulting crude was purified over silica gel column
chromatography with 60% EtOAc in hexane, which afforded
product 6g (49 mg, 16%) & 4l (200 mg, 64%).
4
.4.11. tert-butyl 3-(6,8-dibromo-5-cyano-2H-
benzo[b][1,4]oxazin-4(3H)-yl)propylcarbamate
(
6g):
o
4
.4.7. 6,8-dibromo-4-butyl-3,4-dihydro-2H-
Colourless solid (49 mg, 16%); mp: 116-118 C; R = 0.4
f
benzo[b][1,4]oxazine-5-carbonitrile (6e):
1
(30% EtOAc in hexane); H NMR (400 MHz, CDCl ) δ = 7.31
3
o
Colourless solid (15 mg, 19%); mp: 112-114 C; Rf = 0.6
(s, 1H), 4.90 (br. s., 1H), 4.26 - 4.18 (m, 2H), 3.45 - 3.34 (m,
1
1
3
(15% EtOAc in hexane); H NMR (400 MHz, CDCl ) δ = 7.28
3
2H), 3.30 - 3.20 (m, 4H), 2.07 - 1.92 (m, 2H), 1.43 (s, 9H); C
NMR (100 MHz, CDCl ) δ = 156.2, 143.2, 142.1, 127.3, 117.1,
(s, 1 H), 4.23 (t, J = 4.4 Hz, 2H), 3.4 (t, J = 8.3 Hz, 2H), 3.3 (t, J=
3
4
7
1
1
9
.4 Hz, 2H), 1.84 - 1.72 (m, 2 H), 1.47 - 1.33 (m, 2H), 0.98 (t, J =
1
17.0,116.6, 104.4, 79.3, 62.6, 54.4, 46.2, 37.9, 28.9,
28.4(3xCH3); IR (neat); 3361, 2975, 2220, 1699, 1565, 1510,
441, 1365, 1247, 1168, 1027, 732; HRMS calcd for
13
.3 Hz, 3H); C NMR (100 MHz, CDCl ) δ = 142.9, 142.0,
3
26.6, 117.6, 116.8, 116.2, 103.7, 62.9, 56.5, 46.7, 30.5, 19.8,
3.9; IR (neat); 2958, 2867, 2218, 1567, 1439, 1367, 1235, 1031,
11, 732; HRMS calcd for C H Br N O: 372.9551, found
1
+
C H Br N O : 474.0028, found [M+H] :474.0017.
17
22
2
3
3
13
15
2
2
+
4.4.12. tert-butyl 3-(6,8-dibromo-7-cyano-2H-
benzo[b][1,4]oxazin-4(3H)-yl)propylcarbamate
(4l):
[
M+H] :372.9533.
4
.4.8. 6,8-dibromo-4-butyl-3,4-dihydro-2H-
o
benzo[b][1,4]oxazine-7-carbonitrile (4j):
Colourless solid (200 mg, 64%); mp: 98-100 C. R = 0.2
f
o
1
Colourless solid (52 mg, 63%); mp: 124-126 C; R = 0.8 (15%
f
(30% EtOAc in hexane); H NMR (400 MHz, CDCl ) δ = 6.73
(s, 1H), 4.67 (br. s., 1H), 4.29 (t, J = 4.4 Hz, 2 H), 3.49 (t, J = 4.4
Hz, 2 H), 3.37 (t, J = 7.3 Hz, 2 H), 3.20 (q, J = 6.4 Hz, 2H), 1.82
3
1
EtOAc in hexane); H NMR (400 MHz, CDCl )  = 6.72 (s, 1H),
3
4
2
0
1
1
1
.27 (t, J = 4.4 Hz, 2H), 3.48 (t, J = 4.4 Hz, 2H), 3.31 (t, J = 7.3 Hz,
H), 1.59 (dt, J = 7.3, 15.1 Hz, 2H), 1.37 (qd, J = 7.4, 14.9 Hz, 2H),
13
(quin, J = 7.1 Hz, 2 H), 1.48 (s, 9 H); C NMR (100 MHz,
13
.97 (t, J = 7.3 Hz, 3H); C NMR (100 MHz, CDCl ) δ =139.9,
3
CDCl ) δ= 156.1, 139.9, 139.7, 118.8, 117.5, 113.6, 112.9, 104.5,
7
3
1256, 1167, 1062, 929; HRMS calcd for C17
4
3
39.6, 118.9, 117.7, 113.4, 112.9, 113.8, 64.2, 50.8, 46.7, 28.2, 20.2,
3.9; IR (neat); 2956, 2930, 2217, 1580, 1507, 1458, 1348, 1304,
9.7, 64.3, 48.4, 46.7, 38.1,31.4, 28.4(3XCH3), 27.0 ; IR (neat);
352, 2974, 2935, 2218, 1697, 1584, 1511, 1462, 1353, 1306,
257, 1206, 1127, 1062, 920, 823, 700; HRMS calcd for
+
H22Br
2
N
3
O
3
:
C H Br N O: 372.9551, found [M+H] :372.9546.
13
15
2
2
+
74.0028, found [M+H] :474.0021.
6
f and 4k:
To solution of 2,4,6-tribromo-3-(2-bromoethoxy)benzonitrile 8a
150 mg, 0.32 mmol) in DMF (2 mL) was added ethanaloamine (118
6
h and 4m:
(
To
solution
of
a
2,4,6-tribromo-3-(2-
o
mg, 1.94 mmol) and the reaction mixture is stirred for 10h at 85 C.
To the reaction mixture then added water (6 mL) and extracted with
EtOAc (12x3 mL). The combined organic phases were washed with
water (3 mL), brine (3 mL), dried over sodium sulfate and
bromoethoxy)benzonitrile 8a (100 mg, 0.216 mmol) in DMF (1
mL) was added cyclopropylamine (62 mg, 1.082 mmol) and the
reaction mixture is stirred for 3h at 90 C. To the reaction mixture
o

1
1
then added water (3 mL) and extracted with
A
EtO
C
A
C
c
E
(8
P
x3TEmL
D
). MA
m
N
g,
U
1.0
S
8
C
m
R
mo
I
l
P
) and the reaction mixture is stirred for 40h at rt.
T
The combined organic phases were washed with water (2 mL),
brine (2 mL), dried over sodium sulfate and concentrated in
vacuo. The resulting crude was purified over silica gel column
chromatography with 12% EtOAc in hexane, which afforded
product 6h (25 mg, 32%) & 4m (42mg,54%).
To the reaction mixture then added water (6 mL) and extracted with
EtOAc (12x3 mL). The combined organic phases were washed with
water (3 mL), brine (3 mL), dried over sodium sulfate and
concentrated in vacuo. The resulting crude was purified over silica
gel column chromatography with 25% EtOAc in hexane, which
afforded product 6j (38 mg, 20%) & 4o (40 mg, 77%).
4
.4.13. 6,8-dibromo-4-cyclopropyl-3,4-dihydro-2H-
4.4.17. 4-(2-(1H-indol-3-yl)ethyl)-6,8-dibromo-3,4-
dihydro-2H-benzo[b][1,4]oxazine-5-carbonitrile
benzo[b][1,4]oxazine-5-carbonitrile (6h):
o
(
6j):
Colourless solid (25 mg, 32%); mp: 152-154 C; R = 0.5 (5%
f
1
o
EtOAc in hexane); H NMR (400 MHz, CDCl ) δ = 7.17 (s, 1H),
4
1
Colourless solid (38 mg, 20%); mp: 154-156 C; R
EtOAc in hexane); H NMR (400MHz ,DMSO-d
6
1
7
1
f
= 0.5 (10%
) δ = 10.85 (br. s.,
H), 7.65 (d, J = 7.8 Hz, 1H), 7.47 (s, 1H), 7.33 (d, J = 7.8 Hz, 1H),
.16 (d, J = 2.0 Hz, 1H), 7.06 (dt, J = 1.0, 7.6 Hz, 1H), 6.97 (dt, J =
.0, 7.3 Hz, 1H), 4.22-4.20 (m, 2H), 3.63 - 3.56 (m, 2H), 3.39 - 3.35
3
1
.19 (t, J = 3.9 Hz, 2H), 3.52 (t, J = 4.2 Hz, 2H), 3.32 - 3.22 (m,
13
H), 1.11 - 1.00 (m, 2H), 0.82 - 0.72 (m, 2H); C NMR (100
MHz, CDCl ) δ = 141.7, 141.9, 124.9, 117.7, 117.5, 114.8, 100.1,
3
6
1
8
5.5, 47.2, 35.8, 11.8(2XCH); IR (neat); 3087, 2984, 2938, 2216,
568, 1472, 1443, 1356, 1288, 1259, 1227, 1104, 1023, 909,
30,733; HRMS calcd for C H Br N O: 356.9238, found
13
(m, 2H), 3.20 - 3.13 (m, 2 H); C NMR (100 MHz, DMSO-d ) δ =
6
1
42.9, 142.3, 136.1, 127.1, 125.7, 123.0, 121.0, 118.4, 118.3, 117.0,
116.2, 115.7, 111.3, 110.8, 102.7, 62.9, 57.2, 46.28, 24.1; IR (neat);
397, 2217, 1650, 1567, 1441, 1363, 1233, 1022, 998, 744; HRMS
12
11
2
2
+
[
M+H] :356.9229.
3
+
4
.4.14. 6,8-dibromo-4-cyclopropyl-3,4-dihydro-2H-
calcd for C19H16Br N O: 459.9660, found [M+H] :459.9647.
2 3
benzo[b][1,4]oxazine-7-carbonitrile (4m):
4.4.18. 4-(2-(1H-indol-2-yl)ethyl)-6,8-dibromo-3,4-
dihydro-2H-benzo[b][1,4]oxazine-7-carbonitrile
o
Colourless solid (42 mg, 54%); mp: 250-252 C; R = 0.2 (5%
f
1
(4o):
EtOAc in hexane); H NMR (400 MHz, CDCl ) δ = 7.27(s, 1H)
4
1
MHz, CDCl ) δ = 141.1, 140.2, 118.1, 117.4, 115.3, 113.1, 106.0,
6
1
3
o
Colourless solid (40 mg, 77%); mp: 154-156 C; R = 0.2 (10%
EtOAc in hexane); H NMR (400MHz ,DMSO-d ) δ = 10.85 (br. s.,
.31 (t, J = 4.4 Hz, 2H), 3.44 (t, J = 4.4 Hz, 2H), 2.53 - 2.44 (m,
f
1
13
6
H), 1.00 - 0.92 (m, 2H), 0.73 - 0.65 (m, 2 H); C NMR (100
1
2
1
H), 7.55 (d, J = 7.8 Hz, 1H), 7.35 (d, J = 8.3 Hz, 1H), 7.19 (d, J =
.4 Hz, 1H), 7.08 (td, J = 1.0, 7.6 Hz, 1H), 6.99 (td, J = 1.0, 7.8 Hz,
3
5.3, 45.8, 31.4, 8.3(2XCH2); IR (neat); 2966, 2217,1585, 1497,
H), 6.91 (s, 1H), 4.13 (t, J = 4.4 Hz, 2H), 3.69 (t, J = 7.1 Hz, 2H),
412, 1354, 1331, 1263, 1214, 1067, 1030, 833, 706; HRMS
13
+
3.40 (t, J = 4.4 Hz, 2H), 2.97 (t, J = 6.8 Hz, 2H); C NMR (100
calcd for C H Br N O: 356.9238, found [M+H] :356.9233.
12
11
2
2
MHz, DMSO-d ) δ = 140.4, 139.2,136.2, 127.0, 123.3, 121.0, 118.4,
6
1
4
1
18.2, 118.0, 117.7, 112.8, 112.2, 111.5, 110.8, 101.0, 63.8, 50.7,
6.1, 21.4; IR (neat); 3398, 2217, 1583, 1513, 1423, 1349, 1258,
022, 998, 823, 751; HRMS calcd for C H Br N O: 459.9660,
6
i and 4n:
To solution of 2,4,6-tribromo-3-(2-bromoethoxy)benzonitrile
a (150 mg, 0.32 mmol) in DMF (2 mL) was added 4-
8
19 16
2
3
+
found [M+H] :459.9648.
.4.19. (S)-6,8-dibromo-4-(1-phenylethyl)-3,4-
dihydro-2H-benzo[b][1,4]oxazine-7-carbonitrile
4p):
To solution of 2,4,6-tribromo-3-(2-bromoethoxy)benzonitrile
a (100 mg, 0.216 mmol) in DMF (2 mL) was added (S)-(-)- α-
methoxybenzylamine (267 mg, 1.94 mmol) and the reaction
mixture is stirred for 48h at rt. To the reaction mixture then
added water (6 mL) and extracted with EtOAc (15x3 mL). The
combined organic phases were washed with water (3 mL), brine
4
(
(3 mL), dried over sodium sulfate and concentrated in vacuo. The
8
resulting crude was purified over silica gel column
chromatography with 25% EtOAc in hexane, which afforded
product 6i (21 mg, 15%) & 4n (90 mg, 63%).
methylbenzylamine (79 mg, 0.649 mmol) and the reaction
o
mixture is stirred for 20h at 100 C. To the reaction mixture then
added water (4 mL) and extracted with EtOAc (8x3 mL). The
combined organic phases were washed with water (2 mL), brine
4
.4.15. 6,8-dibromo-4-(4-methoxybenzyl)-3,4-
dihydro-2H-benzo[b][1,4]oxazine-5-carbonitrile
(2 mL), dried over sodium sulfate and concentrated in vacuo. The
(
6i):
resulting crude was purified over silica gel column
o
Colourless solid (21 mg, 15%); mp: 156-158 C; R = 0.6
chromatography with 13% EtOAc in hexane, which afforded
f
1
o
(10% EtOAc in hexane); H NMR (400 MHz, CDCl ) δ = 7.43
product 4p as colourless solid (42 mg, 46%); mp: 162-164 C; R
3
f
1
(s, 1H), 7.40 (d, J = 8.3 Hz, 2H), 6.92 (d, J = 8.3 Hz, 2H), 4.49
= 0.6 (10% EtOAc in hexane); H NMR (400 MHz, CDCl ) δ=
3
(
s, 2H), 4.18 (t, J=4.4Hz, 2H), 3.82 (s, 3 H), 3.1 (t, J=4.4 Hz,
7.47 - 7.22 (m, 5H), 5.12 (q, J = 6.8 Hz, 1H), 4.27 (ddd, J = 3.2,
4.6, 10.8 Hz, 1H), 4.11 (ddd, J = 2.9, 7.5, 10.6 Hz, 1H), 3.33
(ddd, J = 2.9, 7.3, 12.7 Hz, 1H), 3.12 (ddd, J=2.9, 7.3,12.7 Hz,
13
2
1
5
1
H); C NMR (100 MHz, CDCl ) δ = 159.5, 144.1, 141.2,
3
30.0(2XCH), 128.0, 116.9, 116.3, 114.2(2XCH), 106.8, 62.1,
9.5, 55.3, 44.6; IR (neat); 3071, 2898, 2835, 2222, 1610, 1562,
13
1H), 1.62 (d, J=6.8 Hz, 3H); C NMR (100 MHz, CDCl ) δ=
3
511, 1439, 1249, 1176, 1015, 902, 731; HRMS calcd for
140.0,139.99, 139.2, 129.0(2XCH), 128.1, 126.8(2XCH), 118.9,
117.5, 113.9, 113.5, 104.7, 64.6, 55.3, 40.3, 15.9; IR (neat);
+
C H Br N O : 435.9422, found [M+H] :438.9366.
17
14
2
2
2
2
979,2219,1579, 1454, 1307, 1258, 1205, 1064, 705; HRMS
4
.4.16. 6,8-dibromo-4-(4-methoxybenzyl)-3,4-
dihydro-2H-benzo[b][1,4]oxazine-7-carbonitrile
4n):
+
calcd for C H Br N O: 420.9551, found [M+H] :420.9535.
17
15
2
2
(
4
.4.20. (R)-6,8-dibromo-4-(1-phenylethyl)-3,4-
o
Colourless solid (90 mg, 63%); mp: 150-152 C; R = 0.8 (10%
EtOAc in hexane); H NMR (400 MHz, CDCl ) δ = 7.13 (d, J = 8.8
Hz, 2H), 6.9 (d, J=8.7 Hz, 2H), 6.83 (s, 1H), 4.49 (s, 2H), 4.32 (t,
J=4.4 Hz, 2H), 3.81 (s, 3H), 3.49(t, J=4.4Hz, 2H); C NMR (100
dihydro-2H-benzo[b][1,4]oxazine-7-carbonitrile
(4q):
f
1
3
To solution of 2,4,6-tribromo-3-(2-bromoethoxy)benzonitrile
a (100 mg, 0.216 mmol) in DMF (2 mL) was added (R)-(-)- α-
13
8
MHz, CDCl ) δ = 159.4, 140.2, 139.8, 128.1, 126.9, 118.9, 117.5,
3
methylbenzylamine (79 mg, 0.649 mmol) and the reaction
mixture is stirred for 20h at 100 C. To the reaction mixture then
added water (4 mL) and extracted with EtOAc (8 x 3 mL). The
combined organic phases were washed with water (2 mL), brine
1
2
14.6, 113.7, 113.5, 104.8, 64.4, 55.3, 53.7, 46.4; IR (neat); 2938,
838, 1583, 1510, 1459, 1348, 1305, 1250, 1207, 1032, 821; HRMS
o
+
calcd for C H Br N O : 435.9422, found [M+H] :436.9488.
17
14
2
2
2
6
j and 4o:
To solution of 2,4,6-tribromo-3-(2-bromoethoxy)benzonitrile 8a
100 mg, 0.216 mmol) in DMF (2 mL) was added tryptamine (173
(2 mL), dried over sodium sulfate and concentrated in vacuo. The
resulting crude was purified over silica gel column
(

1
2
Tetrahedron
chromatography with 13% EtOAc in hexan
A
e,
C
w
C
hic
E
h
P
affo
T
E
rd
D
ed MApu
NU
rif
hexane, which afforded products 9a-9c.
.5.1. (R)-2,4,6-tribromo-3-(2-(1-
phenylethylamino)ethoxy)benzonitrile (9a):
Colourless liquid; (52 mg, 32%); R =0.2(10% EtOAc in hexane); H
NMR (400 MHz, CDCl ) δ =7.87 (s, 1H), 7.41 - 7.32 (m, 4H), 7.31 -
ied
S
o
C
ve
R
r s
I
i
P
lic
T
a gel column chromatography with 15% EtOAc in
o
product 4q as colourless solid (40 mg, 44%); mp: 162-164 C; R
=
f
1
4
0.6 (10% EtOAc in hexane); H NMR (400 MHz, CDCl ) δ =
3
7
4
.45 - 7.08 (m, 5H), 5.05 (q, J = 6.8 Hz, 1H), 4.26 - 4.14 (m, 1H),
.04 (ddd, J = 2.7, 7.7, 10.6 Hz, 1H), 3.26 (ddd, J = 2.9, 7.5, 12.6
1
f
Hz, 1H), 3.07 (td, J = 3.7, 12.7 Hz, 1H), 1.55 (d, J = 6.8 Hz, 3H);
3
13
7
2
.23 (m, 1H), 4.19 - 4.06 (m, 2H), 3.91 (q, J = 6.8 Hz, 1H), 2.99 -
.89 (m, 2H), 1.97 (br. s., 1H), 1.42 (d, J=6.8 Hz, 3H); C NMR
C NMR (100 MHz, CDCl ) δ = 140.03,140.0, 139.2,
3
1
3
1
1
1
29.0(2XCH), 128.1, 126.8(2XCH), 118.8, 117.5, 113.8, 113.5,
04.6, 64.6, 55.3, 40.3, 15.9; IR (neat); 3058, 2979, 2219, 1579,
495, 1453, 1305, 1258, 1204, 934, 702; HRMS calcd for
(100 MHz, CDCl ) δ = 153.9, 145.2, 136.4, 128.5, 127.1, 126.7,
3
1
24.4, 123.1, 121.1, 119.3, 115.4, 73.6, 58.0, 47.2, 24.5; IR (neat);
+
3055, 2965, 2234, 1580, 1494, 1428, 1345, 1264, 1024, 731, 699;
HRMS calcd for C H Br N O: 500.8813, found [M+H] :500.8808.
C H Br N O: 420.9551, found [M+H] :420.9547.
17
15
2
2
+
17
16
3
2
4
.4.21. 5-benzyl-7,9-dibromo-2,3,4,5-
tetrahydrobenzo[b][1,4]oxazepine-8-carbonitrile
4r):
To solution of 2,4,6-tribromo-3-(3-bromopropoxy)benzonitrile
b (70 mg, 0.147 mmol) in DMF (1.5 mL) was added
4.5.2. (S)-2,4,6-tribromo-3-(2-(1-
phenylethylamino)ethoxy)benzonitrile (9b):
1
(
Colourless liquid; (52 mg, 32%); R = 0.2(10% EtOAc in hexane); H
f
NMR (400 MHz, CDCl
) δ = 7.85 (s, 1H), 7.38 - 7.31 (m, 4H), 7.28 -
3
7
2
.22 (m, 1H), 4.18 - 4.06 (m, 2H), 3.89 (q, J = 6.8 Hz, 1H), 3.02 -
.85 (m, 2H), 1.92 (s, 1 H), 1.44 - 1.36 (d, J= 6.8 Hz, 3H); C NMR
8
1
3
benzylamine (84 mg, 0.783 mmol) and the reaction mixture is
stirred for 12h at 110 C. To the reaction mixture then added
water (6 mL) and extracted with EtOAc (12x3 mL). The
combined organic phases were washed with water (3 mL), brine
o
(100 MHz, CDCl ) δ = 153.9, 145.2, 136.4, 128.5, 127.1, 126.7,
3
1
3
7
24.4, 123.1, 121.1, 119.3, 115.4, 73.6, 58.0, 47.2, 24.5; IR (neat);
064, 3026, 2962, 2232, 1580, 1552, 1495, 1426, 1343, 1246, 1021,
63, 734, 697; HRMS calcd for C H Br N O: 500.8813, found
17
16
3
2
(3 mL), dried over sodium sulfate and concentrated in vacuo. The
+
[
M+H] :500.881.
.5.3. 2,4,6-tribromo-3-(2-
diallylamino)ethoxy)benzonitrile (9c):
Colourless liquid; (95 mg, 61%); R = 0.3(10% EtOAc in hexane); H
NMR (400 MHz, CDCl ) δ = 7.86 (s, 1 H), 5.87 (tdd, J = 6.4, 10.4,
resulting crude was purified over silica gel column
chromatography with 10% EtOAc in Hexane, which afforded
product 4r as colourless solid (34 mg, 55%); mp: 146-148 C; R
=
4
(
o
f
1
1
f
0.3 (10% EtOAc in hexane); H NMR (400 MHz, CDCl ) δ =
3
3
7
.39 (t, J = 7.3 Hz, 2H), 7.33 (d, J = 6.8 Hz, 1H), 7.22 (d, J = 7.3
1
7.0 Hz, 2H), 5.28 - 5.09 (m, 4H), 4.09 (t, J = 6.4 Hz, 2H), 3.23 (d, J
Hz, 2H), 4.50 (s, 2 H), 4.31 (t, J = 6.4 Hz, 2H), 3.6 (t, J=5.8 Hz,
2
13
=
6.4 Hz, 4H), 2.99 (t, J = 6.4 Hz, 2H); C NMR (100 MHz, CDCl3)
δ = 154.2, 136.3, 135.3 (2xCH), 124.5, 123.2, 121.0, 119.2, 117.9
2xCH2), 115.5, 72.0, 57.5 (2xCH2), 52; IR (neat);3073, 2808, 2235,
641, 1551, 1425, 1425, 1346, 1247, 1156, 994, 919, 867, 737, 697;
13
H), 2.09 (quin, J = 6.1 Hz, 2H); C NMR (100 MHz, CDCl ) δ
3
=
1
(
148.3, 144.8, 136.1, 129.1(2XCH), 127.8, 126.9(2XCH),
20.9, 120.5, 118.7, 117.2, 107.1, 70.3,56.8, 49.3, 27.6; IR
neat);3061, 3028, 2950, 2219, 1570, 1492, 1453, 1337, 1279,
(
1
+
HRMS calcd for C H Br N O: 476.8813, found [M+H] :476.8805.
15 16 3 2
1
4
279, 1227, 1181, 950,729; HRMS calcd for C H Br N O:
20.9551, found [M+H] : 420.9534.
4.6. General follow up experimental procedures and spectral
data for the compounds 4p, 4q and 4g:
17
15
2
2
+
4
.4.22. 5-allyl-7,9-dibromo-2,3,4,5-
4
.6.1. (S)-6,8-dibromo-4-(1-phenylethyl)-3,4-
dihydro-2H-benzo[b][1,4]oxazine-7-carbonitrile
4p):
A solution of compound 9b (20 mg, 0.039 mmol) in DMF (0.5
tetrahydrobenzo[b][1,4]oxazepine-8-carbonitrile
(
4s):
(
To solution of 2,4,6-tribromo-3-(3-bromopropoxy)benzonitrile
b (70 mg, 0.147 mmol) in DMF (1 mL) was added allylamine
o
8
mL) is heated to 100 C for 12h.To the reaction mixture then
added water (2 mL) and extracted with EtOAc (8x2 mL). The
combined organic phases were washed with water (2 mL), brine
(42 mg, 0.783 mmol) and the reaction mixture is stirred for 8h at
o
9
0 C. To the reaction mixture then added water (4 mL) and
extracted with EtOAc (8x3 mL). The combined organic phases
were washed with water (3 mL), brine (3 mL), dried over sodium
sulfate and concentrated in vacuo. The resulting crude was
purified over silica gel column chromatography with 25% EtOAc
in Hexane, which afforded product 4s as colourless solid (34 mg,
(
2 mL), dried over sodium sulfate and concentrated in vacuo. The
resulting crude was purified over silica gel column
chromatography with 30% EtOAc in hexane, which afforded
product 4p as colourless solid (13 mg, 76%); mp: 162-164 C; R
=
7.47 - 7.22 (m, 5H), 5.12 (q, J = 6.8 Hz, 1H), 4.27 (ddd, J = 3.2,
4.6, 10.8 Hz, 1H), 4.11 (ddd, J = 2.9, 7.5, 10.6 Hz, 1H), 3.33
o
f
1
0.6 (10% EtOAc in hexane); H NMR (400 MHz, CDCl ) δ=
3
o
1
6
2%); mp: 150-152 C; R = 0.3(20% EtOAc in hexane); H
f
NMR (400 MHz, CDCl ) δ = 6.76 (s, 1H), 5.82 (tdd, J = 4.5,
3
1
0.5, 17.1 Hz, 1H), 5.29 (qd, J = 1.5, 10.3 Hz, 1H), 5.23 - 5.15
(ddd, J = 2.9, 7.3, 12.7 Hz, 1H), 3.12 (ddd, J=2.9, 7.3,12.7 Hz,
13
(
3
m, 1H), 4.29 (t, J = 6.3 Hz, 2H), 3.88 (td, J = 1.6, 4.6 Hz, 2H),
.62 - 3.54 (m, 2H), 2.19 - 2.07 (m, 2H); C NMR (100 MHz,
1
1
H), 1.62 (d, J=6.8 Hz, 3H); C NMR (100 MHz, CDCl ) δ=
3
13
40.0,139.99, 139.2, 129.0(2XCH), 128.1, 126.8(2XCH), 118.9,
CDCl ) δ =147.9, 144.5, 131.6, 120.8, 120.3, 118.3, 117.7, 117.2,
3
117.5, 113.9, 113.5, 104.7, 64.6, 55.3, 40.3, 15.9; IR (neat);
979,2219,1579, 1454, 1307, 1258, 1205, 1064, 705; HRMS
1
1
06.6, 70.2, 55.4, 48.9, 27.6; IR (neat); 2960, 2869, 2216, 1573,
2
+
501, 1452, 1337, 1279, 1189, 1052, 955, 727; HRMS calcd for
calcd for C H Br N O: 420.9551, found [M+H] :420.9535.
17
15
2
2
+
C H Br N O: 370.9395, found [M+H] :370.9382.
13
13
2
2
4
.6.2. (R)-6,8-dibromo-4-(1-phenylethyl)-3,4-
4
.5. Experimental procedures and spectral data for the
dihydro-2H-benzo[b][1,4]oxazine-7-carbonitrile
compounds 9a-9c:
(4q):
Employing above procedure 20 mg of 9a gave 4q (14 mg,
To solution of 2,4,6-tribromo-3-(2-bromoethoxy)benzonitrile 8a
o
8
2%) as colourless solid, mp: 162-164 C; R = 0.6 (10% EtOAc
f
(150 mg, 0.324 mmol) in DMF (2 mL) was added (R)-(-)- α-
1
in hexane); H NMR (400 MHz, CDCl ) δ = 7.45 - 7.08 (m, 5H),
methylbenzylamine (118 mg, 0.972 mmol) and the reaction mixture
is stirred for 18h at rt . To the reaction mixture then added water (4
mL) and extracted with EtOAc (8x3 mL The combined organic
phases were washed with water (2 mL), brine (2 mL), dried over
sodium sulfate and concentrated in vacuo. The resulting crude was
3
5
.05 (q, J = 6.8 Hz, 1H), 4.26 - 4.14 (m, 1H), 4.04 (ddd, J = 2.7,
7.7, 10.6 Hz, 1H), 3.26 (ddd, J = 2.9, 7.5, 12.6 Hz, 1H), 3.07 (td,
13
J = 3.7, 12.7 Hz, 1H), 1.55 (d, J = 6.8 Hz, 3H); C NMR (100
MHz, CDCl ) δ = 140.03,140.0, 139.2, 129.0(2XCH), 128.1,
3
1
26.8(2XCH), 118.8, 117.5, 113.8, 113.5, 104.6, 64.6, 55.3, 40.3,

1
3
1
1
5.9; IR (neat); 3058, 2979, 2219, 1579, 1495,
A
14
C
53
C
, 1
E
30
P
5
T
, 1
E
25
D
8, MA
m
N
mo
U
l)
S
an
C
d
R
2MIP
K CO (aq) (0.2 mL) after degassing reaction
2 3
o
T
204, 934, 702; HRMS calcd for C H Br N O: 420.9551, found
mixture is stirred at 80 C. To the reaction mixture after 12h was
added (3 mL) water and extracted with EtOAc (12x3 mL)The
combined organic phases were washed with (3 mL) brine (3 mL),
dried over sodium sulfate and concentrated in vacuo The
resulting crude was purified over silica gel column
chromatography with 10% EtOAc in hexane, which afforded
17
15
2
2
+
[
M+H] :420.9547.
4
.6.3. 4-allyl-6,8-dibromo-3,4-dihydro-2H-
benzo[b][1,4]oxazine-7-carbonitrile (4g):
Employing above procedure 20 mg of 9c gave 4g (12mg,
o
8
0%), Colourless solid; mp: 138-140 C. R = 0.2 (10% EtOAc in
o
f
product 10c as colourless solid (28 mg, 81%) mp: 138-140 C;
1
hexane); H NMR (400 MHz, CDCl ) δ = 6.72 (s, 1H), 5.79 (tdd,
J = 5.1, 10.3, 17.1 Hz, 1H), 5.23(dd, J=10.2, 17.6 Hz, 2H), 4.32
1
3
R =0.6 (10% EtOAc in hexane); H NMR (400 MHz, CDCl ) δ =
f
3
7
4
.62 - 7.53 (m, 4H), 7.51 - 7.37 (m, 6H), 6.98 (s, 1H), 4.22 (t, J =
(
t, J=4.4 Hz, 2H), 3.95 (d, J=4.9 Hz, 2H), 3.49 (t, J=4.4 Hz, 2H);
13
.4Hz, 2H), 3.34 (t, J = 4.4Hz, 2H), 3.29 - 3.24 (m, 3H);
C
1
3
C NMR (100 MHz, CDCl ) δ= 139.9, 139.8, 130.3, 118.8,
3
NMR (100 MHz, CDCl ) 143.4, 141.6, 139.6, 138.8, 136.9,
34.1, 129.4, 129.0, 128.5, 128.2, 128.17, 128.0, 123.8, 118.3,
01.7, 61.4, 50.1, 44.9; IR (neat); 3057, 2927, 2215, 1588, 1554,
3
1
2
9
18.0, 117.5, 113.5, 113.5, 64.4, 53.1, 46.5; IR (neat); 3088,
879, 2216, 1583, 1511, 1458, 1349, 1308, 1260, 1208, 1063,
26, 822; HRMS calcd for C H Br N O: 356.9238, found
1
1
1
12
11
2
2
464, 1404, 1371, 1270, 1213, 1080, 1009, 773, 700; HRMS
+
[
M+H] :356.9227.
+
calcd for C H N O: 327.1497, found [M+H] :327.1492.
2
2
19
2
4
.7. Experimental procedures and spectral data for the
5
. Acknowledgements
compounds 10a -10c:
FAK gratefully acknowledges DBT for financial support.
MAP thanks CSIR for the award of a fellowship.
4
2
.7.1. 4-methyl-7-nitro-6,8-diphenyl-3,4-dihydro-
H-benzo[b][1,4]oxazine (10a):
To solution of 4f (22 mg, 0.063 mmol) in dioxane (1 mL) was
added Pd(PPh ) (14 mg, 0.0125 mmol), PhB(OH) (16 mg, 0.125
3
4
2
6
. References
mmol) and 2M K CO (aq) (0.2 mL) after degassing under argon,
2
3
o
reaction mixture is stirred at 80 C. To the reaction mixture after
0h was added (3 mL) water and extracted with EtOAc (10x3
1
.
(a) Beletskaya I. P; Ananikov V. P. Chem. Rev., 2011, 111, 1596;
1
(
b) Brachet E.; Hamze A.; Peyrat J-F.; Brion J-D.; Alami M., Org.
Lett., 2010, 12, 4042; (c) Zhang P.; Le C.; MacMillan D. W. C. J.
Am. Chem. Soc., 2016, 138, 8084.
mL). The combined organic phases were washed with (2 mL)
brine, dried over sodium sulfate and concentrated in vacuo. The
resulting crude was purified over silica gel column
chromatography with 20% EtOAc in hexane, which afforded
2
3
.
.
Fehe´r D.; Barlow R.; McAtee J.; Hemscheidt T. K.J. Nat. Prod.,
2
010, 73, 1963.
Won T. H.; Jeon J.; Kim S.-H.; Lee S. –H.; Rho B. J.; Oh D.-C.;
o
product 10a as yellow solid (12 mg, 55%); mp: 154-156 C;
Oh K.-B.; Shin J. J. Nat. Prod. 2012, 75, 2055.
1
R =0.5 (20% EtOAc in hexane); H NMR (400 MHz, CDCl ) δ =
4. (a) Khan F. A.; Ahmad S. J. Org. Chem., 2012, 77, 2389; (b)
Khan F. A.; Ahmad S. Tetrahedron Lett., 2013, 54, 2996; (c)
Khan F. A.; Ahmad S.; Kodipelli N.; Shivange G.; Anindya R.
Org. Biomol. Chem., 2014, 12, 3847.
f
3
7
3
.48 - 7.31 (m, 10 H), 6.57 (s, 1 H), 4.25 (t, J = 4.4Hz, 2 H),
.39(t, J = 4.4Hz, 2 H), 3.01 (s, 3 H); C NMR (100 MHz,
13
CDCl ) δ = 139.9,137.9, 133.0, 129.4(2xCH), 128.6(2xCH),
3
5
.
Norbert M.; Werner L.; Sylvie P.; Pierre S.; Schwartz J. C.;
1
4
1
28.3, 128.2(2xCH), 128.1(2xCH), 127.9, 123.1, 111.8, 64.8,
8.5, 38.7; IR (neat); 3057, 2935, 1588, 1517, 1351, 1305, 1234,
056, 700; HRMS calcd for C H N O : 347.1396, found
Holger S. Eur. J. Med. Chem., 1999, 34, 791.
6. Hayakawa I.; Hiramitsu T.; Tanaka Y. Chem. Pharm. Bull., 1984,
2, 4907.
3
21
19
2
3
+
7. Largeron M.; Lockhart B.; Pfeiffer B.; Fleury M.B. J. Med.
Chem., 1999, 42, 5043.
[
M+H] :347.1392.
8
.
(a) Touzeau F.; Arrault A.; Guillaumet G.; Scalbert E.; Pfeiffer B.;
Rettori M. C.; Renard P.; Me´rour J. Y. J. Med. Chem., 2003, 46,
4
.7.2. 4-allyl-6,8-diphenyl-3,4-dihydro-2H-
benzo[b][1,4]oxazine-7-carbonitrile (10b):
1
962; (b) Combs D. W.; Rampulla M. S.; Bell S. C.; Klaubert D.
To solution of 4g (35 mg, 0.097 mmol) in (1 mL) dioxane was
H.; Tobia A. J.; Falotico R.; Haertlein B.; Weiss C. L.; Moore J.
B. J. Med. Chem., 1990, 33, 381; (c) S¡tefanic¡P.; Turns¡ek K.;
Kikelj D. Tetrahedron, 2003, 59, 7123; (d) Zhangqin L.;Yuanwei
C. Tetrahedron Lett., 2009, 50, 3790; (e) Malgorzata S.; Halina K.
Current Organic Synthesis, 2014, 11, 676; (f) Jun Y.; Simin Y.;
Shanshan Z.; Dongbo L.; Liyan J.; Zhongjun L.; Siwang Y.;
added Pd(PPh ) (22 mg, 0.0194 mmol), PhB(OH) (24 mg, 0.194
mmol) and 2M K CO (aq) (0.2 mL) after degassing under argon
3
4
2
2
3
o
reaction mixture is stirred at 80 C. To the reaction mixture after
2h was added water (3 mL) and extracted with EtOAc (8x3
1
mL). The combined organic phases were washed with brine (2
mL), dried over sodium sulfate and concentrated in vacuo. The
resulting crude was purified over silica gel column
chromatography with 25% EtOAc in hexane, which afforded
product 10b as colourless solid (18 mg, 52%); mp: 84-86 C;
R =0.4(25% EtOAc in hexane); H NMR (400 MHz, CDCl ) δ =
7
5
-
Xiangbao M. Eur. J. Med. Chem., 2016, 122, 488
(a) Hili R.; Yudin A. K. J. Am. Chem. Soc., 2009, 131, 16404; (b)
He Z.; Zajdlik A.; Yudin A. K. Acc. Chem. Res., 2014, 47, 1029.
.
9
.
10. Domling A. Chem. Rev. 2006,106, 17.
1
o
1. (a) Rolfe A.; Samarakoon T. B.; Hanson P. R. Org. Lett., 2010,
12, 1216. (b) Samarakoon T. B.; Hur M. Y.; Kurtz R. D.; Hanson
P. R. Org. Lett., 2010, 12, 2183. (c) Loh J. K.; Asad N.;
1
f
3
.62 - 7.54 (m, 2 H), 7.52 - 7.35 (m, 8 H), 6.67 (s, 1 H), 5.95 -
Samarakoon T. B.; Hanson P. R. J. Org. Chem., 2015, 80, 9926.
.77 (m, 1 H), 5.33 - 5.21 (m, 2 H), 4.21 (t, J= 4.4 Hz, 2 H), 4.06
12. Kottakota S. K.; Evangelopoulos D.; Alnimr A.; Bhakta S.;
McHugh T. D.; Gray M.; Groundwater P. W.; Marrs E. C. L.;
Perry J. D.; Spilling C. D.; Harburn J. J. J. Nat. Prod., 2012, 75,
13
3.95 (m, 2H), 3.48 (t, J= 4.8Hz , 2H); C NMR (100 MHz,
CDCl ) δ 140.7, 139.60, 139.55, 138.7, 135.1(2xCH), 133.7,
3
1
090.
1
1
4
1
31.4,
130.1,
129.0(2XCH),
128.5(2XCH),
128.2,
1
1
1
3. Crystallographic data (excluding structure factors) for the
structures in this paper have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication nos.
CCDC 1493027 (4a) and CCDC 1493028 (6h).
4. (a) Smith, M. B.; March, J. March’s Advanced Organic
Chemistry: Reactions, Mechanisms, and Structure,6th ed.; John
Wiley & Sons, Inc.: New York, 2007; pp 853. b) Bunnett J. F. Q.
Rev. Chem. Soc., 1958, 12, 1.
28.14(2xCH), 128.06, 119.1, 117.5, 111.8, 99.0, 64.1, 53.2,
6.8; IR (neat);3058, 2925, 2210, 1589, 1498, 1440, 1351, 1240,
069, 699; HRMS calcd for C H N O: 353.1654, found
24
21
2
+
[
M+H] :353.1643.
4
.7.3. 4-methyl-6,8-diphenyl-3,4-dihydro-2H-
benzo[b][1,4]oxazine-5-carbonitrile (10c):
5. Osuna M. R.; Aguirre G.; Somanathan R.; Molins E. Tetrahedron:
Asymmetry, 2002, 13, 2261.
To solution of 6a (35 mg, 0.105 mmol) in dioxane (1 mL) was
added Pd(PPh ) (12 mg, 0.0105 mmol), PhB(OH) (26 mg, 0.210
3
4
2

14
Tetrahedron
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Table 1

ACCEPTED MANUSCRIPT
Table 2

ACCEPTED MANUSCRIPT
Table 3
Table 4
R
R
X
X
Pd(PPh ) 0.2 eq
3 4
PhB(OH) 2 eq
2
O
2
M K CO3
O
2
N
Dioxane
N
Me
o
8
0 C
Me
NO2
CN
N
CN Me
N
O
O
O
N
Me
10a, 55%
10b, 53%
10c, 81%